CSF proteomics of the APPPS1 Alzheimer mouse model with life long BACE inhibition

The earliest defining event in the pathogenesis of Alzheimer´s disease (AD) is the intracerebral deposition of Abeta, which starts at least 20 years before the onset of dementia. The link between Abeta and downstream neurodegeneration leading to dementia remains unclear, a critical gap in knowledge at a time when clinical trials are increasingly shifting to pre-symptomatic disease stages. Consequently, the design of preventive treatment strategies based on biomarkers remains an important challenge. Here, we have analyzed CSF samples from 21.5-month-old APPPS1 and WT mice, with and without BACE inhibition from 1.5 to 21.5 months, using mass spectrometry-based label-free quantification of proteins. Life-long BACE inhibition showed a partial rescue of several CSF protein markers for neurodegeneration such as NEFL and inflammation such as Trem2 or Cst7.

阿尔茨海默病（AD）发病机理的最早定义事件是Abeta在内脑中的沉积，该过程至少在痴呆症状出现前20年开始。Abeta与导致痴呆的下游神经退行性变之间的联系尚不明确，这在临床试验日益转向无症状疾病阶段的同时，成为知识体系中的一个关键空白。因此，基于生物标志物的预防治疗策略的设计仍然是一项重要挑战。在本研究中，我们利用基于质谱的无标记蛋白质定量技术，分析了从1.5个月至21.5个月期间，APPPS1和WT小鼠的脑脊液样本，并考虑了有无BACE抑制剂的情况。终身BACE抑制剂的应用显示出对神经退行性相关脑脊液蛋白标记物，如NEFL，以及炎症相关标记物，如Trem2或Cst7的局部挽救作用。